CoA is synthesized in mammalian cells from the vitamin, pantothenate. Our in vivo experiments with rats and mice have demonstrated that the total CoA contents of heart and liver (and possibly kidney and adipose tissue) change with fasting, feeding, alloxan and genetic diabetes, insulin and exercise. Our studies with rat liver parenchymal cells in primary culture have shown that total CoA levels in liver are regulated by glucagon in a cAMP-mediated action enhanced by glucocorticoids, and by insulin. In addition, we have discovered that a class of metabolites which includes ethanol and acetaldehyde decrease total CoA levels in the cultured cells and inhibit incorporation of [14C]-pantothenate into CoA. Our present research objectives are to determine (1) how glucagon, glucocorticoids and/or insulin regulate the CoA content of heart and liver (2) to investigate the role of this regulation in tissue function, in conservation of body pantothenate, and in minimizing the effects of pantothenate deficiency on metabolic performance, and (3) to assess the implications of hormonal control over pantothenate utilization for the normal population, for individuals with diabetes mellitus, and for chronic alcoholic patients. Our investigations into the mechanism of hormonal and metabolite regulation will involve identifying by direct enzyme assay, and by kinetic studies, the individual enzymes of the biosynthetic and/or degradative pathways which are regulated. To understand the rationale behind the hormonal regulation of total CoA levels, we will determine which metabolic pathways in cultured liver cells are affected by decreasing CoA independently of hormonal status through pantothenate deprivation, and by comparing the effects of starvation and refeeding on certain metabolic pathways in tissues and organelles from rats and mice maintained on different dietary levels of pantothenate. We will also determine whether blood tests for pantothenate-CoA status reflect disturbances of pantothenate utilization (absorption and conversion to CoA), and use these tests to screen for abnormal pantothenate utilization in diabetic and chronic alcoholic patients.